Parenterals PDF

Parenterals Objectives Know/understand in full all the method of sterilizing. Understand which dosage forms use which method of sterilization. Which of the main parenteral ROA’s have the fastest onset time? Slowest? What are cryoprotectant used for? Under...

Parenterals Objectives Know/understand in full all the method of sterilizing. Understand which dosage forms use which method of sterilization. Which of the main parenteral ROA’s have the fastest onset time? Slowest? What are cryoprotectant used for? Understand what lyophilization is? What are some examples of a cryoprotectant? Understand what a pyrogen is. Know which solvents and vehicles are acceptable or not acceptable for parenteral formulations Understand what can happen if you mix two incompatible ingredients. Parenterals-USP definition Parenteral articles are preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal, so that the active substances they contain are administered, using gravity or force, directly into a blood vessel, organ, tissue, or lesion. Parenteral articles are prepared by scrutinized methods designed to ensure that they meet Pharmacopeial requirements for sterility, pyrogens, particulate matter, and other contaminants, and, where appropriate, contain inhibitors of the growth of microorganisms.  Some Reasons for Parenterals When the API would be rapidly broken-down in the GI track and become inactivated before it could be absorbed into systemic circulation. Gentamicin is an example of this. To provide a highly localized effect. (example: intra-ocular injections) Fast/rapid onset For hydration and electrolyte replacement TPN Considerations They must be: Isotonic Sterile Must be practically free of endotoxins and pyrogens Free of visual particulates and very low numbers of sub- visible particles Use of colorants as additives is strictly prohibited: why is this? Physiological Barriers Skin Airways GI tract Liver  Advantages They are used to by-pass the normal defense mechanisms Rapid onset (by IV route) Predictable and complete bioavailability (*If IV) Can be used in unconscious patients, those that are NPO, those that cannot swallow or are uncooperative Can be a ROA for drugs that are ineffective via other routes Can offer a local effect (example: Novocaine) Disadvantages Expensive Must be sterile: prepared in special hoods Require trained personnel Difficult to remove if adverse or toxic reaction Patient acceptability – not a preferred method by patients Potential introduction of micro-organisms/toxins (potentially fatal- especially if the patient is already very sick and/or has a poor immune system) Thrombosis (coagulation or clotting of the blood), air emboli (air bubbles in a vein or artery; can cause blockage), hemolysis (when red blood cells rupture), precipitation in the vein, extravasation (cytotoxics), tissue/nerve damage* Most Important Factors From a Pharmaceutical Scientist Point of View Drug Solubility and our ability to incorporate into a dosage form may be more limited. If passive diffusion, Fick’s First law applies Partition Coefficient Ionization: need for dissolution vs absorption Precipitation in the blood stream should not occur! Osmolarity Ability to Sterilize without causing stability issues Excipient concentration and “FDA limits”  Typical Formula API Buffers, agents to adjust pH Sometimes preservatives Sometimes Antioxidants Sometimes organic solvents to solubility (volume varies depending on solvent but as minimal as possible.) Water for injection (Several types) Diluent/Buffer Examples of Small Volume Parenterals Available in vials, pre-filled syringes/pens or ampules. (2 to 30 ml) Examples: Heparin sodium, insulin, lidocaine HCL If reconstituted, the dry weight of the powder typically does not affect total volume. More on this in calculations course. Large Volume Parenterals Administered via IV infusion to maintain or replenish body fluids, electrolytes, provide nutrition. Can also incorporate a medication into these fluids. Usually in volumes of 100 ml to 1 L Examples: NaCl (1/2NS, NS), Dextrose (D5W), Mannitol, LR  Dialysis Solutions Requires same level of sterility as parenterals. Are typically large volumes (Example: 2.5 L, 5 L) They typically have different package types to avoid selecting the wrong product. Sometimes dispensed by pharmacy. Depends on where you work and the hospital system. Regardless, are typically kept separate from the IV solutions to prevent medical error. Irrigation Solutions Irrigation solutions are used to bathe, wash wounds or surgical incisions or body tissues. Occasionally need to be compounded Irrigation solutions are typically screw-capped bottles to allow easy pouring. Again, they typically have different package types to avoid selecting the wrong product. Irrigation solutions that are used to wash wounds are not typically subjected to the same level of sterility. I.E. Do NOT administer them IV.  Powders for injections Are dry solid, sterile substances When dispensed, a volume of the prescribed sterile diluent (usually an aqueous liquid) is added and shaken with the powder. This should rapidly form either a clear, particle-free solution or a uniform suspension. (Note: there are some cases where you need time to form a solution of suspension) Freeze-dried (lyophilized): used for drug substances that are not stable in solution. The drug in a solution is sterilized and then frozen. A vacuum is applied so that the water in the drug solution is removed by sublimation, leaving the sterile dry powder. Common cyroprotectants: Mannitol, Lactose, Sucrose, Trehalose, Glycine, Histadine, Tween (for proteins/biologicals). Cyroprotectants help to stabilize and protect from the effects of freezing.  ROAs IV i. Most rapid onset ii. Complete bioavailability iii. Bolus dosing or infusion (LVPs) iv. Aqueous solutions, fat emulsions v. Less irritation IM i. Easier administration than IV ii. Slower onset but prolonged action than IV iii. Limited volumes up to ~4 mL iv. Osmolarity essential, no dilution occurs v. Aqueous or oleaginous solutions, suspensions & emulsions Intradermal i. Volumes up to 0.2 mL ii. Absorption is slow iii. Used for immunological diagnostic tests, allergy tests, TB, some vaccines  Subcutaneous (SC) i. Slower onset than IM ii. But fairly rapid and predictable absorption iii. Technically simpler iv. ↓ discomfort & ↓ risk of complications than IM v. Volumes up to ~1 mL vi. Narrow control of pH and tonicity vii. Solutions, suspensions & emulsions viii. Drugs ineffective orally, insulin, vaccines Figure VI-3. Linear Plot of Cp versus Time Showing Bolus, Infusion, and Combined Curves The plasma concentration time curve is as shown in Figure VI-3 Formulation-Solvents and Vehicles Solvents and Vehicle ‘Water for injection’ is the most common: sterile & Pyrogen free. However, there are multiple types. Non aqueous vehicles – Used when limited water solubility – Drugs susceptible to hydrolysis – Water miscible solvents – glycerin, propylene glycol, alcohol, etc. – Vegetable oils (IM) – soybean oil, corn oil, peanut oil, sesame oil, olive oil, etc. (ex: some can be used for/in IM injections)  We never use mineral oil or paraffin in IV formulations. (Why? They are not absorbed by body tissues) Too toxic for use: Ethylene glycol; don’t confuse this with polyethylene glycol. Additional info about the use of oils The USP requires that they remain clear when heated and then cooled to 10 oC (50 oF)* These oils can cause allergic reactions in some patients. Formulation: Tonicity/pH adjusters Must be isotonic solution to avoid destruction of red blood cells, irritation, and tissue damage The larger the volume administered, the more important this becomes. Buffers – Physiologically compatible – Ideal pH = 7.4 (>pH 9 may get tissue damage and < pH 3 pain and phlebitis)!!! – To maintain physical stability – improve solubility – To maintain chemical stability – drug stability – Buffers should allow body fluid to change the pH after the injection  Administering drugs that have a high or low pH via a central line can help reduce irritation/inflammation because it becomes rapidly diluted in a large blood volume. (Not super common and not the default). O/W emulsions: depending on their droplet size cannot be administer IV because their droplet size may block the blood capillaries. Some but not all suspensions can be administered IV. (Example: Cefuroxime suspension for IV injection). Water-in-oil emulsions are never administered IV (can cause fat embolism). Common Buffering Agents Used in Parenterals Added to maintain pH for solubility and stability pKa Buffer System 2.1, 7.3, 12.3 Phosphoric acid 3.1, 4.8, 6.4 Citric acid 3.9 Lactic acid 2.11, 4.1, 9.5 Glutamic Acid 4.8 Acetic acid Formulation: Stability Enhancers Co-solvent Improve solubility (~1000 X increase) Prevent potential for hydrolysis Surfactant (surface active agent, wetting agent) Suspension Improve solubility (~100 X increase) Antioxidants (bisulphites, metabisulphites, ascorbic acid) To prevent oxidation Chelating agents (EDTA/citric acid) To remove trace elements that catalyse oxidative degeneration Antimicrobial agents Multiple-dose products To prevent the growth of microorganisms Activity vs. toxicity – esp. for large volumes Interaction with packaging components  Modifying the Formula Use of prodrug Salt form (water soluble) of drug to improve solubility Esterification to prolong drug action Complexation of drug Form complex with cyclodextrans Improve solubility (~500 X increase) Powder for injection (remember lyophilization?) Drug unstable in solution, increases shelf life Emulsion Example: Total Parenteral Nutrition or propofol To solubilize the lipophilic drug or a drug soluble in organic solvent To prolong drug action Suspension Drug insoluble/unstable in aqueous solution To prolong drug action Increase shelf life Other dispersed systems Lipid microspheres, liposomes, microparticulates Physiological Factors Blood flow Influenced by exercise Site of injection (different muscles, SC vs IM) Drugs (vasoconstrictor, etc) Disease (bed bound, CHF,..) Temperature (especially for subcutaneous) Adipose tissue low plasma levels of lidocaine following injection into buttock may be due to high affinity for fatty tissue Gender, age Genetics Food  Container Considerations Transparent to permit visual inspection of content. Materials for the container + seal have the potential to interact with the injection + shed particles. This includes coated vials too! Glass: chemically inert, transparent, strong. Potential for particles to enter injection, especially when opening ampoules. Can be amber bottles; only if necessary. PVC bags: Light, resistant to impact, don’t have problems with vacuums when withdrawing fluid. Adsorb some drugs, require extended sterilization times. Plastic: more drug compatible than PVC, difficult to break Remember: once a pharmaceutical company is approved to use a specific certain container and manufacture….. They are not allowed to change it without FDA approval…. Even if the medication is on back-order and there is no alternative Manufacturing Considerations Environmental controls- – restricted areas, laminar flow cabinets, HEPA filters, etc Personnel issues/requirements- – Major source of contamination – Must be specially trained – Restriction of number of personnel – Protective clothing Sterile, impervious, non-fiber shedding Aseptic technique (reasons why we use and how) – Prevent recontamination of pre-sterilized product components – Avoid direct contact – Reduce airflow disturbances – Use of alcohol – Avoid working over open containers  IV pumps Methods of Sterilization Steam* For preparations and materials that can withstand the required temperatures Preparation must not sensitive to moisture Penetrated by the steam (good for most aqueous products- some exceptions include biologicals and proteins) Generally NOT used for oils, fats, anhydrous powder 121 oC (250 oF) for at least 20 minutes at 15 psi (*min temp required depends on the pressure setting of the machine) Dry Heat* (At least) 160°C for >2 hours. Can vary – i.e. higher temp for shorter periods or vice versa Consider size, type of product, heat distribution characteristic Heat-stable, non-aqueous preparations, powders, oils, and dry equipment's Filtration – Removes most bacteria, molds, and particles, but may allow viruses, small bacteria, and pyrogens to pass through – Application-aqueous products that cannot be heat sterilized – Cannot be used for suspensions or small volumes of potent drugs – Only used when other methods are not suitable – 0.22 micron filter or less Gas – Ethylene Oxide – Active against all microbes – Ethylene oxide is an alkylating agent that disrupts the DNA of microorganisms – Activity depends on concentration, temperature, humidity, and length of exposure – Application: Suitable for thermolabile + moisture-sensitive substances, and can sterilize a wide range of materials – Disadvantages: slow, high running costs, hazards associated with flammability + toxicity, potential production of toxic substances with some materials  Radiation – Application: Tends to be used for articles not sterilizable by other methods – syringes, catheters, etc. – Not usually used for pharmaceuticals as can cause destruction of product, color changes, alterations in texture or solubility – May be useful for sterilizing vaccines without loss of antigenicity In-Process Sterilization – Keeping everything sterile from the very start – May or may not be feasible – Expensive Biologics- sterilization After a biologic is produced, it usually needs sterilization. It is most often injected subcutaneously. The preferred method for sterilization with delicate proteins and other biomolecules, is filter sterilization using a